Nitrogen-containing heterocycles are prevalent in numerous biologically active products that are the bases and templates for countless pharmaceuticals and other compounds used in many disciplines, including medicinal chemistry. Among the many pharmaceutical uses of nitrogen-containing heterocycles, many of these compounds have been identified as serotonin 5-HT3 antagonists, including ondansetron, palonosetron, granisetron, tropisetron, and dolasetron, depicted below.

Often, one enantiomer of a nitrogen-containing heterocycle is primarily responsible for the biological activity of a racemate; the other enantiomer generally exhibits less or even no activity. In addition, different stereoisomers of a compound often exhibit other differences in biological activity. Accordingly, a stereo- and enantioselective synthesis of a target compound is typically a more efficient way to produce chiral pharmaceuticals or other compounds. However, stereo- and enantioselective syntheses of many nitrogen-containing heterocyclic compounds can be difficult. While some stereoselective methods for the synthesis of certain nitrogen-containing heterocycles and their cyclic amine derivatives are known, fewer enantioselective methods exist. Additionally, many of these stereoselective methods use chiral auxiliaries specific to particular functional groups, which is less mass-efficient and/or cost-effective.
The 5-HT3 receptor is a membrane-bound ligand-gated ion channel whose natural ligand is serotonin. The inhibitors depicted above are highly selective against other 5-HT receptor subtypes, and act by preventing excitation of the vagus nerve in the medulla oblongata, which induces vomiting. These drugs are commonly administered in combination with chemotherapeutics to reduce nausea and vomiting.
The pharmacophore for 5-HT3 receptor antagonists consists of three chemical moieties, as depicted in FIG. 1. The N-containing heteroaromatic moiety is proposed to participate in cation-π interaction with a protonated arginine residue of the protein. The basic nitrogen moiety, in its protonated form, is proposed to participate in a cation-π interaction with tyrosine and tryptophan residues of the protein. The hydrogen bond acceptor, which in ondansetron is the carbonyl group, is proposed to participate in a hydrogen bonding interaction with a network of bound water molecules.
There is a need for methods that would allow access to chemical scaffolds having a basic structural analogy to the ondansetron pharmacophore, particularly enantioselective methods to provide enantioenriched products.